Substituted piperazines,(1,4) diaszepines, and 2,5-diazabicyclo (2.2.1)iieptanes as histamine h1 and/or h3 antagonists or histamine h3 reverse antagonists

ABSTRACT

The present invention relates to novel piperazine and azepine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurodegenerative disorders including Alzheimer&#39;s disease.

The present invention relates to novel piperazine and azepinederivatives having pharmacological activity, processes for theirpreparation, to compositions containing them and to their use in thetreatment of neurodegenerative disorders including Alzheimer's disease.

WO 02/76925 (Eli Lilly) describes a series of compounds which areclaimed to be histamine H3 antagonists. WO 02/055496 (GlaxoSmithKline)describes a series of piperidine and piperazine derivatives which areclaimed to be inducers of LDL-receptor expression. WO 02/12214 (OrthoMcNeil Pharmaceutical Inc) describes a series of substitutedaryloxyalkylamines which are claimed to be histamine H3 antagonists.

The histamine H3 receptor is expressed in both the mammalian centralnervous system (CNS), and in peripheral tissues (Leurs et al., (1998),Trends Pharmacol. Sdi. 19, 177-183). Activation of H3 receptors byselective agonists or histamine results in the inhibition ofneurotransmitter release from a variety of different nerve populations,Including histaminergic, adrenergic and cholinergic neurons (Schlickeretal., (1994), Fundam. Clin. Pharmacol. 8, 128-137). Additionally, invitro and in vivo studies have shown that H3 antagonists can facilitateneurotransmitter release in brain areas such as the cerebral cortex andhippocampus, relevant to cognition (Onidera et al., (1998), in: TheHistamine H3 receptor, ed Leurs and Timmerman, pp255-267, ElsevierScience B.V.). Moreover, a number of reports in the literature havedemonstrated the cognitive enhancing properties of H3 antagonists (e.g.thioperamide, clobenpropit, ciproxifan and GT-2331) in rodent modelsincluding the five choice task, object recognition, elevated plus maze,acquisition of novel task and passive avoidance (Giovanni et al.,(1999), Behav. Brain Res. 104, 147-155). These data suggest that novelH3 antagonists and/or inverse agonists such as the current series couldbe useful for the treatment of cognitive impairments in neurologicaldiseases such as Alzheimer's disease and related neurodegenerativedisorders.

The present invention provides, in a first aspect, a compound of formula(I):

wherein:

R¹ represents hydrogen, —C₁₋₈ alkyl, —C₁₋₆ alkoxy, —C₃₋₈ cycloalkyl,—C₁₋₈ alkyl-C₃₋₈ cycloalkyl, aryl, heterocyclyl, heteroaryl, —C₁₋₆alkyl-aryl, —C₁₋₆ alkyl-heteroaryl, —C₁₋₆ alkyl-heterocyclyl,-aryl-aryl, -aryl-heteroaryl, -aryl-heterocyclyl, -heteroaryl-aryl,-heteroaryl-heteroaryl, -heteroaryl-heterocycyl, -heterocyclyl-aryl,-heterocyclyl-heteroaryl, -heterocyclyl-heterocyclyl,

wherein R¹ may be optionally substituted by one or more substituentswhich may be the same or different, and which are selected from thegroup consisting of halogen, hydroxy, COOR¹⁵, cyano, —C₁₋₆ alkyl-cyano,nitro, oxo, trifluoromethyl, trifluoromethoxy, fluoromethoxy,difluoromethoxy, C₁₋₆ alkyl (optionally substituted by a COOR¹⁵ group),C₂₋₆ alkenyl (optionally substituted by a COOR¹⁵ group), C₂₋₆ alkynyl(optionally substituted by a COOR¹⁵ group), C₁₋₆ alkoxy (optionallysubstituted by a COOR¹⁵ group), pentafluoroethyl, C₁₋₆ alkoxy, C₂₋₆alkenoxy, aryl, arylC₁₋₆ alkyl, —CO-aryl (optionally substituted by ahalogen atom), —CO-heteroaryl, —C₁₋₆ alkyl-CO-aryl, arylC₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl,sulfonyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC₁₋₆ alkyl,aryloxy, C₁₋₆ alkylsulfonamido, C₁₋₆ alkylamido, C₁₋₆alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆ alkylamidoC₁₋₆ alkyl, arylsulfonamido,arylcarboxamido, arylsulfonamidoC₁₋₆ alkyl, arylcarboxamidoC₁₋₆ alkyl,aroyl, aroylC₁₋₆ alkyl, arylC₁₋₆ alkanoyl, or a group —COR¹⁵, —NR¹⁵R¹⁶,—CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —NR¹⁵SO₂R¹⁶ or —SO₂NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶independently represent hydrogen, C₁₋₆ alkyl or C₃₋₈ cycloalkyl ortogether may be fused to form a 5- to 7-membered non-aromaticheterocyclic ring optionally interrupted by an O or S atom andoptionally substituted by a halogen, C₁₋₆ alkyl or —C₁₋₆ alkylC₁₋₆alkoxy group;

Z represents a bond, CO₁ N(R¹⁰)CO or SO₂, such that when R¹ representshydrogen, Z represents NR¹⁰CO;

p is 1 or 2;

m, n and r independently represent 0, 1 or 2;

R² represents halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino ortrifluoromethyl, such that when n represents 2, two R² groups mayinstead be linked to form a phenyl ring;

R⁴ represents C₁₋₆ alkyl, or when r represents 2, two R⁴ groups mayinstead together form a bridged CH₂, (CH₂)₂ or (CH₂)₃ group;

R¹⁰ represents hydrogen or C₁₋₆ alkyl, or R¹⁰, together with thenitrogen to which it is attached and R¹ forms a nitrogen containingheterocyclic group;

R³ represents —(CH₂)_(q)—NR¹¹R¹² or a group of formula (I):

wherein q is 2, 3 or 4;

R¹¹ and R12 independently represent C₁₋₆ alkyl or C₃₋₈ cycloalkyl ortogether with the nitrogen atom to which they are attached represent anN-linked nitrogen containing heterocyclyl group optionally substitutedby one or more R¹⁷ groups;

R¹³ represents hydrogen, C₁₋₆ alkyl, —C₁₋₆ alkyl-C₁₋₆ alkoxy, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-aryl orheterocyclyl;

R¹⁴ and R¹⁷ independently represent halogen, C₁₋₆ alkyl, haloalkyl, OH,diC₁₋₆ alkylamino, C₁₋₆ alkoxy or heterocyclyl;

f and k independently represent 0, 1 or 2;

g is 0, 1 or 2 and h is 0, 1, 2 or 3, such that g and h cannot both be0;

with the proviso that when m represents 1, n and r both represent 0 andR³ represents —(CH₂)₃-N-piperidine or —(CH₂)₃-N(ethyl)₂, R¹—Z representsa group other than methyl, —CO—O—C(CH₃)₃ or benzyl;

and with the proviso that when m, n and r all represent 0,p represents1, R³ represents —(CH₂)₃-N-pyrrolidine or —(CH₂)₃-N-piperidine, R¹represents benzyl, Z represents a group other than a bond;

and with the proviso that when m, n and r all represent 0, p represents1, R³ represents —(CH₂)₃-N-piperidine, R¹ represents isopropyl, Zrepresents a group other than a bond;

and with the proviso that when m represents 1, n and r both represent 0,p represents 1,

R³ represents —(CH₂)₃—N-piperidine, R¹ represents methyl, isopropyl,aryl or benzyl, Z represents a group other than a bond;

and with the proviso that when m and n both represent 0, R³ represents—(CH₂)₃— N(ethyl)₂, p represents 1, r represents 2 and R¹ and R⁴ bothrepresent methyl, Z represents a group other than a bond;

or a pharmaceutically acceptable salt thereof.

In one particular aspect of the present invention, there is provided acompound of formula (I) as defined above wherein:

R¹ represents a group other than hydrogen, —C₁₋₆ alkoxy or —C₁₋₆alkyl-C₃₋₆ cycloalkyl; and

R¹ is optionally substituted by one or more substituents other thanCOOR¹⁵, —C₁₋₆ alkyl-cyano, C₁₋₆ alkyl substituted by a COOR¹⁵ group),C₂₋₆ alkenyl (optionally substituted by a COOR¹⁵ group), C₂₋₆ alkynyl(optionally substituted by a COOR¹⁵ group), C₁₋₆ alkoxy (optionallysubstituted by a COOR¹⁵ group), C₂₋₆ alkenoxy, aryl, arylC₁₋₆ alkyl,—CO-aryl (optionally substituted by a halogen atom), —CO-heteroaryl,—C₁₋₆ alkyl-CO-aryl or C₃₋₇ cycloalkyl; and

R¹⁵ and R¹⁶ independently represent a group other than C₃₋₈ cycloalkylor together may be fused to form an unsubstituted 5- to 7-memberednon-aromatic heterocyclic ring optionally interrupted by an O or S atom;and

r represents 0; and

two R² groups are not linked to form a phenyl ring; and

R¹¹ and R¹² independently represent a group other than C₃₋₈ cycloalkyl;and

R¹³ represents a group other than —C₁₋₆ alkyl-C₃₋₈ cycloalkyl.

In a second particular aspect of the present invention, there isprovided a compound of formula (I) as defined above wherein m represents0 or 2.

In a further particular aspect of the present invention, there isprovided a compound of formula (I) as defined above wherein Z representsCO, CONR¹⁰ or SO₂.

Alkyl groups, whether alone or as part of another group, may be straightchain or branched and the groups alkoxy and alkanoyl shall beinterpreted similarly. Alkyl moieties are more preferably C₁₋₄ alkyl,eg. methyl or ethyl. The term ‘halogen’ is used herein to describe,unless otherwise stated, a group selected from fluorine, chlorine,bromine or iodine.

The term “aryl” includes single and fused rings wherein at least onering is aromatic, for example, phenyl, naphthyl, tetrahydronaphthalenyl,indanyl or fluorenyl.

The term “heterocyclyl” is intended to mean a 4-7 membered monocyclicsaturated or partially unsaturated ring or a 4-7 membered saturated orpartially unsaturated ring fused to a benzene ring containing 1 to 3heteroatoms selected from oxygen, nitrogen or sulphur. Suitable examplesof such monocyclic rings include pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrofuranyl, diazepanyl, azepanyland azocanyl. Suitable examples of benzofused heterocyclic rings includeindolinyl, isoindolinyl, benzodioxolyl and dihydroisoquinolinyl.

The term “nitrogen containing heterocyclyl” is intended to represent anyheterocyclyl group as defined above which contains a nitrogen atom.

The term “heteroaryl” is intended to mean a 5-7 membered monocyclicaromatic or a fused 8-11 membered bicyclic aromatic ring containing 1 to3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitableexamples of such monocyclic aromatic rings include thienyl, furyl,pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl,pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such fusedaromatic rings include furopyridinyl and benzofused aromatic rings suchas quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl,naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl,benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl andthe like.

Compounds of formula (I) and their pharmaceutically acceptable saltshave affinity for and are antagonists and/or inverse agonists of thehistamine H3 receptor and are believed to be of potential use in thetreatment of neurological diseases including Alzheimer's disease,dementia, age-related memory dysfunction, mild cognitive impairment,cognitive dysfunction, epilepsy, neuropathic pain, inflammatory pain,migraine, Parkinson's disease, multiple sclerosis, stroke and sleepdisorders including narcolepsy; psychiatric disorders includingschizophrenia, attention deficit hyperactivity disorder, depression andaddiction; and other diseases including obesity, asthma, allergicrhinitis, nasal congestion, chronic obstructive pulmonary disease andgastro-intestinal disorders.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance in the treatment or prophylaxis of the above disorders, inparticular cognitive impairments in diseases such as Alzheimer's diseaseand related neurodegenerative disorders.

Preferably, R¹ represents:

-   -   hydrogen;    -   C₁₋₆ alkyl (eg. methyl, methylbutyl, or propyl);    -   C₁₋₆ alkoxy (eg. —OC(CH₃)₃);    -   aryl (eg. phenyl, naphthyl, tetrahydronaphthyl, indanyl or        fluorenyl);    -   heteroaryl (eg. benzofuranyl, indolyl, pyrazinyl,        benzoxadiazolyl, thiadiazolyl, thienyl, pyrazolopyrimidinyl,        pyrazolopyridinyl, benzothiazolyl, furopyridinyl, pyridyl,        quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, thiazolyl,        triazolyl, isoxazolyl, pyrimidinyl, naphthyridinyl,        benzisoxazolyl or benzisothiazolyl);    -   heterocyclyl (eg. benzodioxolyl, pyrrolidinyl, piperidinyl,        piperazinyl, morpholinyl, thiomorpholinyl,        tetrahydrothiopyranyl, thiopyranyl, tetrahydropyranyl,        dihydrobenzofuranyl, dihydrochromenyl and xanthenyl);    -   C₃₋₈ cycloalkyl (eg. cyclopropyl, cyclopentyl or cyclohexyl);    -   —C₁₋₆ alkyl-aryl (eg. benzyl);    -   —C₁₋₆ alkyl-C₃₋₈ cycloalkyl (eg. —CH₂-cyclopropyl);    -   —C₁₋₆ alkyl-heteroaryl (eg. —CH₂-pyridyl, —CH₂-tetrazolyl,        —CH₂-triazolyl, —CH₂-isothiazolyl, —CH₂-thienyl or        —CH₂-furanyl);    -   -aryl-heterocyclyl (eg. -phenyl-pyrrolidinyl);    -   -aryl-aryl (eg. -biphenyl);    -   -aryl-heteroaryl (eg. -phenyl-pyridyl, -phenyl-pyrrolyl or        -phenyl-tetrazolyl); or    -   -heteroaryl-aryl (eg. -pyridyl-phenyl).

More preferably, R¹ represents unsubstituted phenyl.

Also more preferably, R¹ represents:

-   -   aryl (eg. phenyl); or    -   heterocyclyl (eg. piperidinyl, piperazinyl, morpholinyl,        thiomorpholinyl or tetrahydropyranyl).

Preferably, R¹ is optionally substituted by one or more (eg. 1, 2 or 3):halogen (eg. chlorine, fluorine or bromine); trifluoromethyl; —C₁₋₆alkyl (eg. methyl, ethyl, isopropyl, propyl or t-butyl) optionallysubstituted by COOR¹⁵ (eg. COOH, COOMe or COOEt); —C₁₋₆ alkoxy (eg.methoxy, butoxy, —OCH(Me)₂ or —OC(Me)₃) optionally substituted by COOR¹⁵(eg. COOH or COOMe); hydroxy; oxo; cyano; —C₁₋₆ alkyl-cyano (eg.—CH₂—CN); C₁₋₆ alkenyl (eg. ethenyl) optionally substituted by COOR¹⁵(eg. COOMe); C₃₋₇ cycloalkyl (eg. cyclopentyl); C₁₋₆ alkylsulfonyl (eg.—SO₂Me); C₁₋₆ alkenoxy (eg. —OCH₂CH═CH₂); C₁₋₆ alkylthio (eg. —S-ethyl);NR¹⁵R¹⁶ (eg. N(Me)₂); —C₁₋₆alkyl-aryl (eg. benzyl); aryl (eg. phenyl);—CO-aryl (eg. —CO-phenyl) optionally substituted by halogen (eg.chlorine); —CO-heteroaryl (eg. —CO-azetidinyl); —CO-heterocyclyl (eg.—CO-tetrahydropyranyl); —COOR¹⁵ (eg. COOH, COOMe or COOt-butyl); —COR¹⁵(eg. —CO-methyl, —CO-ethyl, —CO-isopropyl, —CO-cyclopropyl,—CO-cyclobutyl, —CO-cyclopentyl or —CO-cydohexyl); —CONR¹⁵R¹⁶ (eg.—CONH₂, —CO-pyrrolidinyl, —CO-morpholinyl, —CO-piperazinyl,—CO-piperidinyl, —CO-thiomorpholinyl) optionally substituted by C₁₋₆alkyl (eg. methyl), halogen (eg. fluorine) or —C₁₋₆ alkylC₁₋₆ alkoxy(eg. —CH₂-OMe); or —C₁₋₆ alkyl-CO-aryl (eg. —CH₂COphenyl) groups.

More preferably, R¹ is optionally substituted by one or more (eg. 1, 2or 3): halogen (eg. fluorine); oxo; cyano; —CONR¹⁵R¹⁶ (eg.—CO-pyrrolidinyl) or —COR¹⁵ (eg. —CO-isopropyl, —CO-cyclopropyl or—CO-cyclobutyl).

Preferably, Z represents a bond, CO or CONR¹⁰. More preferably, Zrepresents bond or CO, especially CO.

Preferably, R¹⁰ represents hydrogen or C₁₋₆ alkyl.

Preferably, m is 0 or 2, more preferably 0.

Preferably, n is 0 or 1, more preferably n is 0.

When n represents 1, R² is preferably halogen (eg. chlorine, bromine orfluorine), trifluoromethyl, cyano or C₁₋₆ alkyl (eg. methyl).

Preferably, r is 0.

When r represents 1 or 2, R² is preferably C₁₋₆ alkyl (eg. methyl) ortwo R⁴ groups together form a bridged CH₂ group.

Preferably, p is 1.

Preferably, R³ represents —(CH₂)_(q)—NR¹¹R¹².

When R³ represents a group of formula (i), preferably f is 0 or 1, g is2, h is 1, k is 0 and R¹³ represents hydrogen, optionally substitutedC₁₋₆ alkyl (eg. ethyl, methylpropyl, isopropyl or methoxyethyl), C₃₋₈cycloalkyl (eg. cyclopropyl, cyclobutyl or cyclopentyl) or —C₁₋₆alkyl-C₃₋₈ cycloalkyl (eg. —CH₂-cyclopropyl).

When R³ represents a group of formula (i), more preferably f is 0, g is2, h is 1, k is 0 and R¹³ represents C₁₋₆ alkyl (eg. isopropyl) or C₃₋₈cycloalkyl (eg. cyclopropyl or cyclobutyl).

Preferably, q is 2 or 3, more preferably 3.

Preferably, R¹¹ and R¹² independently represent C₁₋₆ alkyl (eg. methyl)or C₃₋₈ cycloalkyl (eg. cyclopentyl) or NR¹¹ R¹² represents aheterocyclic group (eg. piperidinyl, pyrrolidinyl, thiomorpholinyl,azepanyl or azocanyl optionally substituted by one or more halogen (eg.fluorine) or C₁₋₆ alkyl (eg. methyl or ethyl).

More preferably NR¹¹ R¹² represents pyrrolidinyl, piperidinyl, azepanylor azocanyl optionally substituted by one or more C₁₋₆ alkyl (eg. methylor ethyl), especially unsubstituted piperidine.

Preferably, —O—R³ is present at the para position of the phenyl groupwith respect to the rest of the compound.

Preferred compounds according to the invention include examples E1-E503as shown below, or a pharmaceutically acceptable salt thereof.

Compounds of formula (I) may form acid addition salts with acids, suchas conventional pharmaceutically acceptable acids, for example maleic,hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,sulphuric, citric, lactic, mandelic, tartaric and methanesulphonic.Salts, solvates and hydrates of compounds of formula (I) therefore forman aspect of the invention.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of these compounds and themixtures thereof including racemates. Tautomers also form an aspect ofthe invention. For example, when R³ represents (CH₂)_(q)NR¹¹R¹² andNR¹¹R¹² represents a nitrogen containing heterocyclyl group substitutedby one or more C₁ ₈ alkyl groups it will be appreciated that the presentinvention extends to cover diastereomeric and enantiomeric compounds.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

(a) reacting a compound of formula (II)

wherein R¹, Z, R⁴, p, m, r, R² and n are as defined above, with acompound of formula R^(3′)-L¹, wherein R^(3′) is as defined above for R³or a group convertible thereto and L¹ represents a suitable leavinggroup such as a halogen atom (eg. bromine or chlorine) or an optionallyactivated hydroxyl group; or

(b) preparing a compound of formula (I) wherein Z represents CO byreacting a compound of formula (III)

or a protected derivative thereof, wherein R⁴, r, p, m, R², n and R³ areas defined above, with a compound of formula R¹—COX, wherein R¹ is asdefined above and X represents a suitable leaving group such as anactivated hydroxy group, a suitable halogen atom or benzotriazolyl; or

(c) preparing a Compound of formula (I) wherein Z represents SO₂ byreacting a compound of formula (III) as defined above with a compound offormula R¹—SO₂Cl, wherein R¹ is as defined above; or

(d) preparing a compound of formula (I) wherein Z represents NR¹⁰CO byreacting a compound of formula (III) as defined above with a compound offormula R¹—═C═O, wherein R¹ is as defined above; or

(e) preparing a compound of formula (I) wherein Z represents CONR¹⁰ byreacting a compound of formula (III) as defined above, sequentially withphosgene in a solvent such as toluene followed by a compound of formulaR¹⁰R¹—NH, in a solvent such as dichloromethane, wherein R¹ and R¹⁰ areas defined above; or

(f) preparing a compound of formula (I) wherein m represents 1 byreacting a compound of formula (IV)

with a compound of formula (XI)

or an optionally protected derivative thereof, wherein R⁴, r, R², n, R³,R¹, Z and p are as defined above under reducing conditions; or

(g) deprotecting a compound of formula (I) which is protected; and

(h) interconversion to other compounds of formula (I).

When R³ represents —(CH₂)_(q)—NR¹¹R¹², process (a) typically comprisesthe use of a suitable base, such as potassium carbonate in anappropriate solvent such as 2-butanone optionally in the presence of anactivating reagent such as potassium iodide at an appropriatetemperature such as reflux.

When a group R³ convertible to R³ represents, for example,L²—(CH₂)_(q)—, process (a) typically comprises an alkylation reactionusing analogous conditions to those described above.

When R³ represents a group of formula (i) and L¹ represents anoptionally activated hydroxyl group, process (a) typically comprises theuse of a phosphine such as triphenylphosphine in a suitable solvent suchas tetrahydrofuran, followed by addition of an azodicarboxylate such asdiethylazodicarboxylate at a suitable temperature such as roomtemperature.

Process (b) typically comprises the use of an appropriate solvent suchas dichloromethane optionally in the presence of an organic or inorganicbase such as potassium carbonate or in the presence of a suitablecoupling agent such as 1,3-dicyclohexylcarbodiimide and1-hydroxybenzotriazole.

Processes (c) and (d) typically comprise the use of a suitable solventsuch as 2-butanone.

Process (e) typically comprises the use of a suitable base, such astriethylamine.

Process (f) comprises the use of reductive conditions (such as treatmentwith a borohydride eg. sodium triacetoxyborohydride), optionally in thepresence of an acid, such as acetic acid, followed by optionaldeprotection in the event that the compound of formula (XI) is aprotected derivative.

In process (g), examples of protecting groups and the means for theirremoval can be found in T. W. Greene ‘Protective Groups in OrganicSynthesis’ (J. Wiley and Sons, 1991). Suitable amine protecting groupsinclude sulphonyl (e.g. tosyl), acyl (e.g. acetyl,2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl)and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.using an acid such as hydrochloric acid in dioxan or trifluoroaceticacid in dichloromethane) or reductively (e.g. hydrogenolysis of a benzylgroup or reductive removal of a 2′,2′,2′-trichloroethoxycarbonyl groupusing zinc in acetic acid) as appropriate. Other suitable amineprotecting groups include trifluoroacetyl (—COCF₃) which may be removedby base catalysed hydrolysis or a solid phase resin bound benzyl group,such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellmanlinker), which may be removed by acid catalysed hydrolysis, for examplewith trifluoroacetic acid.

Process (h) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation,nucleophilic or electrophilic aromatic substitution, ester hydrolysis oramide bond formation. For example, compounds of formula (I) wherein R³represents a group of formula (i) may be interconverted at the R¹³position by reaction with an alkyl halide such as1-chloro-2-methoxyethane in the presence of a base such as potassiumcarbonate in a suitable solvent such as 2-butanone optionally in thepresence of a transfer reagent such as potassium iodide. Suchinterconversion may also be carried out by reductive amination, forexample, with acetone in the presence of a borohydride such as sodiumtriacetoxyborohydride and optionally an acid such as acetic acid in asuitable solvent such as dichloromethane.

Compounds of formula (II) and (III) wherein m is 1 or 2 may be preparedin accordance with the following scheme:

wherein R⁴, r, R², n, R³, p are as defined above and the compound offormula (V) may be optionally protected.

Step (i) may be performed in an analogous manner to that described forprocess (f) above.

Compounds of formula (III) wherein m is 0 may be prepared in accordancewith the following scheme:

wherein R⁴, r, p, R², n and R³ are as defined above and P¹ represents asuitable protecting group (such as Boc).

Step (i) may be performed when P¹ represents Boc by reacting a compoundof formula (IX) with di-t-butyl carbonate in the presence of a suitablebase (eg. triethylamine) in the presence of a suitable solvent (eg.dichloromethane) at a suitable temperature (eg. room temperature).

Step (ii) may be performed in an analogous manner to the proceduresshown below for the preparation of compounds of formula (IV).

Step (iii) typically comprises a deprotection reaction, for example,when P¹ represents Boc, deprotection may typically comprise reaction ofa compound of formula (III)^(p1) with hydrochloric acid in dioxan ortrifluoroacetic acid In dichloromethane.

Compounds of formula (III) wherein m is 2 may be prepared In accordancewith the following scheme:

wherein R², R³, R⁴, n, p, r are as defined above, p² represents asuitable protecting group such as Boc and L⁵ represents a suitableleaving group such as a halogen atom (eg. bromine).

Step (i) typically comprises reaction of a compound of formula (XII)with a compound of formula (XIII) in the presence of an inert solventsuch as dimethylformamide or acetonitrile.

Step (ii) typically comprises a deprotection reaction, for example, whenP² represents Boc, deprotection may typically comprise reaction of acompound of formula (III)^(pii) with hydrochloric acid in dioxan ortrifluoroacetic acid in dichloromethane.

Compounds of formula (IV) wherein R³ represents —(CH₂)_(q)—NR¹¹R¹² maybe prepared in accordance with the following scheme:

wherein R², n, q, R¹¹, R¹² are as defined above and L¹, L², L³ and L⁴represent suitable leaving groups (eg. halogen atoms, such as bromine orchlorine).

Steps (i), (ii) and (iii) may be performed using similar conditions tothose described for process (a) above.

Compounds of formula (IV) wherein R³ represents a group of formula (i)as defined above may be prepared in accordance with the followingscheme:

wherein R², n, f, g, h, k, are as defined above, L⁴ represents asuitable leaving group such as a halogen atom or a hydroxyl group andR^(13a) is as defined above for R¹³ or a protecting group such ast-butoxycarbonyl, followed by optional deprotection.

Step (i) may be performed using similar conditions to those describedfor process (a) above.

Compounds of formula (II) wherein m is 0 may be prepared by adeprotection reaction of a compound of formula (IX) as defined above,followed by an analogous process to those described in processes (b),(c), (d) and (e) above, optionally followed by hydrolysis treatment tore-generate the free hydroxyl group of formula (II).

Compounds of formula (II) wherein m is 1 or 2 may be prepared from acompound of formula (IV) as defined above in an analogous process tothat defined above to prepare compounds of formula (II)a followed by ananalogous process to those described in processes (b), (c), (d) and (e)above, optionally followed by hydrolysis treatment to re-generate thefree hydroxyl group of formula (II).

Compounds of formula (XI) may be prepared from the correspondingpiperazine or diazepane by analogous procedures to those described inprocesses (b), (c), (d) and (e) above.

Compounds of formula (XI) wherein Z represents a bond may be prepared byreacting a compound of formula R¹-L⁶ (wherein R¹ is as defined above andL6 represents a suitable leaving group, eg. a bromine atom) with acompound of formula (XII), such as 1-BOC-piperazine, in the presence ofa palladium catalyst, such as tris(dibenzylideneacetone) dipalladium,and a ligand such as2-cyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, in an inertsolvent such as tetrahydrofuran and in the presence of a base such aslithium bis(trimethylsilyl)amide in an inert atmosphere (nitrogen) andat elevated temperature such as 80° C., according to the procedure ofBuchwald, Organic Letters, 2002, 4, 2885-2888.

Compounds of formula (V), (VI), (VIII), (IX), (XII) and (XIII) areeither known or may be prepared in accordance with known procedures.

Certain compounds of formula (I), and their pharmaceutically acceptablesalts have also been found to have affinity for the histamine H1receptor.

Histamine H1 receptors are widely distributed throughout the CNS andperiphery, and are involved in wakefulness and acute inflammatoryprocesses [Hill et al, Pharmacol. Rev. 49:253-278 (1997)]. Seasonalallergic rhinitis, and other allergic conditions, are associated withthe release of histamine from mast cells. The activation of Hi receptorsin blood vessels and nerve endings are responsible for many of thesymptoms of allergic rhinitis, which include itching, sneezing, and theproduction of watery rhinorrhea. Antihistamine compounds, i.e. drugswhich are selective H1 receptor antagonists such as chlorphenyramine andcetirizine, are effective in treating the itching, sneezing andrhinorrhea associated with allergic rhinitis, but are not very effectivein treating the nasal congestion symptoms [Aaronson, Ann. Allergy,67:541-547, (1991)].

H3 receptor agonists are known to inhibit the effect of sympatheticnerve activation on vascular tone in porcine nasal mucosa [Varty & Hey.Eur. J. Pharmacol., 452:339-345, (2002)]. In vivo, H3 receptor agonistsinhibit the decrease In nasal airway resistance produced by sympatheticnerve activation [Hey et al, Arzneim-Forsch Drug Res., 48:881-888(1998)]. Furthermore, H3 receptor antagonists in combination withhistamine Hi receptor antagonists reverse the effects of mast cellactivation on nasal airway resistance and nasal cavity volume, an indexof nasal congestion [McLeod et al, Am. J. Rhinol., 13: 391-399, (1999)].A combined histamine H1 and H3 receptor antagonist, such as the seriesdescribed herein, would be effective in the treatment of both the nasalcongestion and the sneezing, itching and rhinorrhea associated with bothseasonal and perennial allergic rhinitis.

Therefore, examples of disease states In which dual histamine H1 and H3antagonists have potentially beneficial anti-inflammatory effectsInclude diseases of the respiratory tract such as asthma (includingallergic and non-allergic), allergic rhinitis, sinusitis, bronchitis(including chronic bronchitis), bronchiectasis, chronic obstructivepulmonary disease (COPD) and cystic fibrosis.

Other examples of disease states in which dual histamine H1 and H3antagonists have potentially beneficial effects include diseases of thegastrointestinal tract such as intestinal inflammatory diseasesincluding inflammatory bowel disease (e.g. Crohn's disease or ulcerativecolitis) and intestinal inflammatory diseases secondary to radiationexposure or allergen exposure.

Dual histamine H1 and H3 antagonists of the present invention may alsobe of use in the treatment of sleep/wake disorders, arousal/vigilancedisorders, migraine, dementia, mild cognitive impairment (pre-dementia),cognitive dysfunction, Alzhelmer's disease, epilepsy, narcolepsy, eatingdisorders, motion sickness, vertigo, attention deficit hyperactivitydisorders, learning disorders, memory retention disorders,schizophrenia, depression, manic disorders, bipolar disorders anddiabetes.

Diseases of principal interest for a dual histamine H1 and H3 antagonistinclude asthma, COPD and inflammatory diseases of the upper respiratorytract involving seasonal and perennial allergic rhinitis, non-allergicrhinitis, and the specific symptoms associated with these diseasesincluding nasal congestion, rhinorrhoea, sneezing, cough and Itching(pruritis) of eyes, ears, nose and throat. Other diseases of principalinterest include cough, chronic urticaria, allergic conjunctivitis,nasal polyposis, sinusitis, psoriasis, eczema and allergic dermatoses(including urticaria, atopic dermatitis, contact dermatitis, drug rashesand insect bites).

Diseases of principal interest include asthma, COPD, cognitive disordersand inflammatory diseases of the upper respiratory tract involvingseasonal and perennial rhinitis.

Preferred diseases of principal interest include asthma, cognitivedisorders and inflammatory diseases of the upper respiratory tractinvolving seasonal and perennial rhinitis.

Further diseases also of principal interest include inflammatorydiseases of the gastrointestinal tract such as inflammatory boweldisease.

Thus the invention also provides a dual histamine H1 and H3 antagonistcompound of formula (I) or a pharmaceutically acceptable salt thereof,for use as a therapeutic substance in the treatment or prophylaxis ofthe above disorders, in particular allergic rhinitis.

Preferred dual histamine H1 and H3 antagonist compounds of formula (I)are those wherein:

R¹ represents aryl (eg. phenyl, naphthyl or tetrahydronaphthyl) orheteroaryl (eg. benzofuranyl, indolyl or quinolinyl);

R¹ is optionally substituted by one or more (eg. 1, 2 or 3): halogen(eg. chlorine, fluorine or bromine); trifluoromethyl; —C₁₋₆ alkyl (eg.methyl, ethyl, isopropyl, propyl or t-butyl) optionally substituted byCOOR¹⁵ (eg. COOEt); —C₁₋₆ alkoxy (eg. methoxy) optionally substituted byCOOR¹⁵ (eg. COOMe); C₁₋₆ alkenyl (eg. ethenyl); NR¹⁵R¹⁶ (eg. N(Me)₂); or

C₁₋₆ alkylthio (eg. —S-ethyl) groups;

Z is a bond or CO;

m is 0 or 2;

n is 0;

r is 0;

p is 1.

R³ represents —(CH₂)_(q)—NR¹¹R¹²;

q represents 3; and

NR¹¹R¹² represents pyrrolidinyl, piperidinyl, azepanyl or azocanyloptionally substituted by one or more C₁₋₆ alkyl (eg. methyl or ethyl),more preferably piperidinyl substituted by one or two methyl or ethylgroups.

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment of the abovedisorders.

When used in therapy, the compounds of formula (I) are usuallyformulated in a standard pharmaceutical composition. Such compositionscan be prepared using standard procedures.

Thus, the present invention further provides a pharmaceuticalcomposition for use in the treatment of the above disorders whichcomprises the compound of formula (I) or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier.

The present Invention further provides a pharmaceutical compositionwhich comprises the compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical compositions according to the invention may also beused in combination with other therapeutic agents, for exampleanti-inflammatory agents (such as corticosteroids (e.g. fluticasonepropionate, beciomethasone dipropionate, mometasone furoate,triamcinolone acetonide or budesonide) or NSAIDs (eg. sodiumcromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotrieneantagonists, lipoxygenase inhibitors, chemokine antagonists (e.g CCR3,CCR1, CCR2, CXCR1, CXCR2 ), iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) orbeta adrenergic agents (such as salmeterol, salbutamol, formoterol,fenoterol or terbutaline and salts thereof), or sympathomimetics (e.gpseudoephedrine or oxymetazoline), or other antagonists at the histaminereceptor (e.g H4), or cholinesterase inhibitors, or cholinergicantagonists, or antiinfective agents (eg. antibiotics, antivirals).

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, topical, parenteral or rectal administrationand, as such, may be in the form of tablets, capsules, oral liquidpreparations, powders, granules, lozenges, reconstitutable powders,injectable or Infusible solutions or suspensions or suppositories.Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be In unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned disorders will vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 200 mg, and such unit doses may be administeredmore than once a day, for example two or three a day. Such therapy mayextend for a number of weeks or months.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

DESCRIPTION 14-[4-(3-Piperldin-1-yl-propoxy)-benzyl]-piperazine-1-carboxylic acidtert-butyl ester (D1)

To a solution of 4-(3-(piperidin-1-yl)propoxy)benzaldehyde (WO 02/12214A2) (1.90 g, 7.68 mmol) in dichloromethane (25 ml) was added 1-N tertbutoxy carbonyl piperazine (1.57 g, 8.45 mmol) followed by acetic acid(1 ml), and the reaction stirred for 1 hour at room temperature, thentreated with sodium triacetoxy borohydride (2 g, 9.61 mmol) and stirredfor 16 hours at room temperature. The reaction was then diluted withsaturated sodium bicarbonate solution and extracted withdichloromethane. The cihloromethane was then washed sequentially withwater and brine, dried over anhydrous sodium sulfate and evaporated invacuo to yield a residue which was purified using silica gelchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the titlecompound (1.586 g, 50%); MS (ES+), m/e 418 [M+H]⁺.

DESCRIPTION 2 1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperazinetrihydrochloride (D2)

To a solution of4-[4-(3-piperidin-1-yl-propoxy)benzyl]-piperazine-1-carboxylic acidtert-butyl ester (D1) (1.576 g, 3.76 mmol) in a (1:1) mixture ofdichloromethane and methanol (20 ml) was added a I M solution ofhydrogen chloride in diethyl ether (20 ml) and the reaction stirred for5 hours at room temperature. The solvent was then evaporated in vacuoand the resulting residue triturated with diethyl ether to afford thetitle compound (1.5 g, 93%); MS (ES+), m/e 318 [M+H]⁺.

DESCRIPTION 34-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane-1-carboxylic acidtert-butyl ester (D3)

The title compound (D3) was prepared from [1,4]diazepane-1-carboxylicacid tert-butyl ester using the method of Description 1 (D1). MS(ES+)m/e 432 [M+H]⁺.

DESCRIPTION 4 1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane(D4)

4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane-1-carboxylic acidtert-butyl ester (D3) (2.27 g, 5.27 mmol) was dissolved indichloromethane (10 ml), treated with trifluoroacetic acid (5ml) andstirred at room temperature under argon for 2 hours. The solvent wasremoved in vacuo and the residue dissolved in methanol and passed downan SCX column (10 g) eluting with methanol followed by 0.88ammonia/methanol (1:9). The basic fractions were combined andconcentrated in vacuo to afford the title compound (1.57 g). MS(ES+) m/e332 [M+H]⁺.

DESCRIPTION 5 4-(4-Formyl-phenoxy)-piperidine-1-carboxylic acidtert-butyl ester (DS)

4-Hydroxybenzaldehyde (2.0 g, 16.4 mmol) was dissolved intetrahydrofuran (20 ml) and treated with4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 20.5mmol) and by column chromatography on silica eluting with 4-1hexane-ethyl acetate to afford the title compound as a colourlessviscous oil (3.8 g) MS (ES+) m/e 355 [M+H]⁺.

DESCRIPTION 104-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester (D10)

A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (D9) (4.0 g; 11.3 mM), piperidine (2.23 ml; 2 eq),potassium carbonate (3.73 g; 2.4 eq) and potassium iodide (3.74 g; 2 eq)in butan-2-one (100 ml) was heated at reflux for 3 days. The mixture wasallowed to cool to room temperature, filtered and evaporated to give thetitle compound as a pale yellow solid (4.6 g) MS (ES+) m/e 404 [M+H]⁺.

DESCRIPTION 11 1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazlne (D11)

A solution of4-[4-(3-piperidin-1-yl-propoxy)phenyl]-piperazine-1-carboxylic acidtert-butyl ester (D10) (1.0 g; 2.48 mM) in trifluoroacetic acid (5 ml)was stirred at room temperature for 60 minutes. The resulting mixturewas purified on an SCX ion exchange cartridge to afford the titlecompound as a colourless crystalline solid (0.76 g) MS (ES+) m/e 304[M+H]⁺.

DESCRIPTION 12 4-(3-Hydroxy-phenyl)-piperazine-1-carboxyllc acidtert-butyl ester (D12)

Prepared from 3-piperazin-1-yl-phenol (Chem. Pharm. Bull. 49(10),1314(2001)) using the same method described in Description 9 (D9). MS (ES+)m/e 279 [M+H]⁺.

DESCRIPTION 13 4-[3-(3-Chloro-propoxy)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (D13)

Prepared from 4-(3-hydroxy-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (D12) using the same method described in Description 9(D9). MS (ES+) m/e 355 [M+H]⁺.

DESCRIPTION 144-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester (D14)

Prepared from 4-[3(3chloro-propoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester (D13) using the same method described in Description 10(D10). MS (ES+) m/e 404 [M+H]⁺.

DESCRIPTION 15 1-[3-(3-Piperidln-1-yl-propoxy)-phenyl]-piperazine (D15)

Prepared from4-[3-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester (D14) using the same method described in Description 11(D11). MS (ES+) m/e 304 [M+H]⁺.

DESCRIPTION 16 4-Bromo-1-methyl-1H-indole (D16)

A solution of 4-bromo-1H-indole (6.7 g) in tetrahydrofuran (75 ml) wastreated with sodium hydride (1.24 g) and stirred for 0.5 h at roomtemperature. The resulting suspension was treated with a solution ofiodomethane (2.34 ml) in tetrahydrofuran (35 ml) at 0° C. and allowed towarm to room temperature over 1 h, whilst stirring. The reaction mixturewas poured onto water and partitioned between dichloromethane and water.The organic phase was dried over (MgSO₄) and concentrated in vacuo toafford the title compound (7.2 g). TLC Silica (cyclohexane-ethyl acetate[1:1]), Rf=0.55.

DESCRIPTION 17 4-Bromo-1-methyl-1H-indole-3-carboxylic acid (D17)

A solution of 4-bromo-1-methyl-1H-indole (D16) (7.0 g) intetrahydrofuran (50 ml) was treated with a solution of trifluoroaceticanhydride (5.65 ml) in tetrahydrofuran (20 ml) at 0° C. The reactionmixture was allowed to warm to room temperature over 6 h, whilststirring. The reaction mixture was concentrated in vacuo and thenre-suspended in ethanol (25 ml). The solution was treated with 5N sodiumhydroxide solution (50 ml) and heated under reflux for 18 h. Thereaction mixture was washed with diethyl ether and the aqueous phaseacidified with 5N hydrochloric acid solution. The precipitate wasfiltered washed with water and concentrated in vacuo to afford the titlecompound (4.88 g). TLC, Silica (cyclohexane-ethyl acetate-acetic acid[3:1:0.1]), Rf=0.35.

DESCRIPTIONS 18-23

Descriptions 18-23 were prepared using analogous methods to Example 76bby substituting 2-methylpiperidine with the appropriate amine.Description Structure RT (min) Mass Ion (M + H)⁺ 18

1.64 332 19

0.65 304 20

1.77 346 21

1.45 318 22

1.57 332 23

1.61 318

DESCRIPTIONS 24-32

Descriptions 24-32 were prepared by analogous methods to those indicatedin the below table: Prepared analogously RT Description Name to (min) 241,1-Dimethylethyl E229a from 3.74 4-(2-naphthalenyl)- known1-piperazinecarboxylate starting materials 25 1,1-Dimethylethyl E229afrom 2.18 & 4-(4-quinolinyl)-1- known 3.02 piperazinecarboxylate and1,1- starting dimethylethyl 4-(3-quinolinyl)-1- materialspiperazinecarboxylate (1:1) 26 1-(2-Naphthalenyl)piperazine E229b from2.00 known starting materials 27 4-(1-Piperazinyl)quinoline and E229bfrom 1.18 3-(1-piperazinyl)quinoline (1:1) D25 283-{[4-(2-Naphthalenyl)-1- E229c from 2.39 piperazinyl]methyl}phenol D2429 3-{[4-(1-Naphthalenyl)-1- E229c from 2.41 piperazinyl]methyl}phenolD26 30 4-{[4-(8-Quinolinyl)-1- E229c from 1.78 piperazinyl]methyl}phenolE229b 31 4-{[4-(4-Quinolinyl)-1- E229c from 1.91piperazinyl]methyl}phenol and D27 3-{[4-(3-quinolinyl)-1-piperazinyl]methyl}phenol (1:1) 32 4-{[4-(1-Naphthalenyl)-1- E229c from2.46 piperazinyl]methyl}phenol D26

DESCRIPTIONS 33-42

Descriptions 33-42 were prepared by analogous methods to those indicatedin the below table: Prepared analogously RT Description Name to (min) 332-Methyl-4-[4-(2-{4- E237a from 2.20 [(phenylmethyl)oxy]phenyl}ethyl)-1-known piperazinyl]quinoline starting materials 34 2-Methyl-4-[4-(2-{3-E237a from 2.11 [(phenylmethyl)oxy]phenyl}ethyl)-1- knownpiperazinyl]quinoline starting materials 35 1-(1-Naphthalenyl)-4-(2-{4-E237a from 2.91 [(phenylmethyl)oxy]phenyl}ethyl) known piperazinestarting materials 36 1-(1-Naphthalenyl)-4-(2-{3- E237a from 2.82[(phenylmethyl)oxy]phenyl}ethyl) known piperazine starting materials 371-Phenyl-4-(2-{4- E237a from 2.55 [(phenylmethyl)oxy]phenyl}ethyl) knownpiperazine starting materials 38 4-{2-[4-(2-Methyl-4-quinolinyl)-1-E237b from 1.69 piperazinyl]ethyl}phenol D33 393-{2-[4-(2-Methyl-4-quinolinyl)-1- E237b from 4.56piperazinyl]ethyl}phenol D34 40 4-{2-[4-(1-Naphthalenyl)-1- E237b from2.28 piperazinyl]ethyl}phenol D35 41 3-{2-[4-(1-Naphthalenyl)-1- E237bfrom 2.32 piperazinyl]ethyl}phenol D36 42 4-[2-(4-Phenyl-1- E237b from2.02 piperazinyl)ethyl]phenol D37

DESCRIPTION 43 3-Bromo-4-ethyl-benzoic acid (D43)

To a mixture of conc. HNO₃ (66 mL), glacial AcOH (300 mL) and water (50mL), 4-ethyl-benzoic acid (15 g) was added, stirring vigorously, beforetreating with bromine (5.67 mL). Finally a solution of AgNO₃ (16.97 g)in water (50 mL) was added dropwise and the mixture was stirredvigorously for 2 h. The precipitate was collected by filtration, washedwell with water, before being extracted with hot, saturatedK₂CO₃solution, and then treated with charcoal. The hot solution wasfiltered through kieselguhr and the solution was acidified to pH1 usingconc. HCl. The resulting white precipitate was collected by filtrationand dried in the vacuum oven overnight at 60° C. to afford the titlecompound (19.46 g). NMR (CDCl₃) δ1.26 (3H, t), 2.83 (2H, q), 7.34 (1H,d), 7.97 (1H, dd), 8.27 (1H, dd)

DESCRIPTION 44 Methyl 3-bromo-4-ethyl-benzoate (D44)

3-Bromo-4-ethyl-benzoic acid (D43) (19.40 g) was dissolved in MeOH (200mL) and then treated with conc. H₂SO₄ (1 mL). The mixture was heated atreflux overnight, and then concentrated under reduced pressure. Theresidue was partitioned between EtOAc and saturated aqueous NaHCO₃solution, extracting again with EtOAc. The combined extracts were thenwashed with brine, dried (MgSO₄). The solvent was evaporated in vacuo toafford the title compound (15.8 g). ¹H NMR (CDCl₃) δ1.24 (3H, t), 2.79(2H, q), 3.91 (3H, s), 7.29 (1H, d), 7.89 (1H, dd), 8.19 (1H, d).

DESCRIPTION 45 Methyl 3-cyano-4ethyl-benzoate (D45)

Methyl 3-bromo-4-ethyl-benzoate (D44) (5 g) in NMP (180 mL) was treatedwith copper (I) cyanide (3.69 g). The mixture was then heated at refluxfor 5 h, under argon. After cooling to 20° C. the reaction mixture wasdiluted with water, then filtered through kieselguhr, washing well withwater and EtOAc. The organic layer was washed with water, brine anddried over MgSO₄. The solvent was evaporated to dryness in vacuo and theresidue was purified by chromatography on silica eluting with EtOAc-Hexane (1:9) to give the title compound (1.9 g) ¹H NMR (CDCl₃) δ1.33(3H, t), 2.94 (2H, q), 3.94 (3H, s), 7.43 (1H, d), 8.17 (1H, dd), 8.28(1H, d).

DESCRIPTION 46 3-Cyano-4-ethyl benzoic acid (D46)

Methyl 3-cyano-4-ethyl-benzoate (D45) (1.92 g) was dissolved in MeOH (50mL) before adding 1M NaOH solution (15.24 mL) and stirring the resultingmixture overnight at room temperature, under argon. The reaction mixturewas diluted with water, and extracted with EtOAc. The aqueous layer wasacidified to pH1 using 2M HCl before extracting with EtOAc. The combinedextracts were washed with brine, dried over MgSO₄ and the solventevaporated to dryness in vacuo to afford the title compound (1.63 g). ¹HNMR (CDCl₃) δ1.35 (3H, t), 2.97 (2H, q), 7.49 (1H, d), 8.24 (1H, dd),8.36 (1H, d).

Analysis of the Examples was performed as follows:

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% formic acid and 0.0M ammonium acetate in water(solvent A) and 0.05% formic acid and 5% water in acetonitrile (solventB), using the following elution gradient 0.0-7min 0% B, 0.7-4.2 min 100%B, 4.2-5.3 min 0% B, 5.3-5.5 min 0% B at a flow rate of 3 mL/min. Themass spectra were recorded on a Fisons VG Platform spectrometer usingelectrospray positive and negative mode (ES+ve and ES−ve).

Preparative mass directed HPLC was conducted on a Waters FractionLynxsystem comprising of a Waters 600 pump with extended pump heads, Waters2700 autosampler, Waters 996 diode array and Gilson 202 fractioncollector on a 10 cm×2.54 cm ID ABZ+column, eluting with 0.1% formicacid in water (solvent A) and 0.1% formic acid in acetonitrile (solventB), using an appropriate elution gradient, at a flow rate of 20 ml/minand detecting at 200-320 nm at room temperature. Mass spectra wererecorded on Micromass ZMD mass spectrometer using electrospray positiveand negative mode, alternate scans. The software used was MassLynx 3.5with OpenLynx and FractionLynx options.

EXAMPLE 11-Phenyl-1-{4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazin-1-yl}-methanone(E1)

N-Cyclohexylcarbodiimide, N-methyl polystyrene HL (200-400 mesh) 1.8mMol/g (650 mg, 1.172 mmol) was suspended in a (1:1) mixture ofdichloromethane and dimethylformamide and treated sequentially withbenzoic acid (72 mg, 0.58 mmol), 1-hydroxybenzotriazole hydrate (80 mg,0.58 mmol) and stirred for 10 minutes at room, temperature. A solutionof 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine trihydrochloride(D2) (125 mg, 0.29 mmol) in dichloromethane (1 ml) and triethylamine(0.13 ml, 0.87 mmol) was then added to the reaction and stirred at roomtemperature for 16 hours. After filtration, the filtrate was applied toa Mega Bond elute SCX ion exchange column washing sequentially withwater and methanol, followed by 0.880 ammonia/methanol (1:10) to elutethe crude reaction mixture. Purification by silica gel chromatographyeluting with a mixture of 0.880 ammonia:methanol:dichloromethane(0.5:4.5:95) to afford the title product (95 mg, 77%); MS (ES+), m/e 422[M+H]⁺.

EXAMPLES 2-11

Examples 2-11 (E2-E11) were prepared from Description 2 (D2) using ananalogous method to that described in Example 1 (E1) by substitutingbenzoic acid for the appropriate acid indicated in the table. ExampleAcid Mass Spectrum 1-Benzo[1,3]dioxol-5-yl-1-{4-[4-(3- piperonylic acidMS (ES+) m/e piperidin-1-yl-propoxy)-benzyl]-piperazin-1- 466 [M + H]⁺yl}-methanone (E2) 1-Naphthalen-2-yl-1-{4-[4-(3-piperidin-1-yl-2-naphthoic acid MS (ES+) m/e propoxy)-benzyl]-piperazin-1-yl}- 472 [M +H]⁺ methanone (E3) 1-(3,5-Dichloro-phenyl)-1-{4-[4-(3-3,5-dichlorobenzoic acid MS (ES+) m/epiperidin-1-yl-propoxy)-benzyl]-piperazin-1- 491/493 [M + H]⁺yl}-methanone (E4) 1-(4-Bromo-3-methyl-phenyl)-1-{4-[4-(3- 3-methyl,4-bromo MS (ES+) m/e piperidin-1-yl-propoxy)-benzyl]-piperazin-1-benzoic acid 515/517 [M + H]⁺ yl}-methanone (E5)1-(2-Methoxy-phenyl)-1-{4-[4-(3-piperidin- 2-methoxy benzoic acid MS(ES+) m/e 1-yl-propoxy)-benzyl]-piperazin-1-yl}- 452 [M + H]⁺ methanone(E6) 1-(3,4-Dichloro-phenyl)-1-{4-[4-(3- 3,4-dichloro MS (ES+) m/epiperidin-1-yl-propoxy)-benzyl]-piperazin-1- benzoic acid 491/493/495yl}-methanone (E7) [M + H]⁺ 4-(1-{4-[4-(3-Piperidin-1-yl-propoxy)-4-cyano benzoic acid MS (ES+) m/e benzyl]-piperazin-1-yl}-methanoyl)-447 [M + H]⁺ benzonitrile (E8)1-(4-Fluoro-phenyl)-1-{4-[4-(3-piperidin-1- 4-fluoro benzoic acid MS(ES+) m/e yl-propoxy)-benzyl]-piperazin-1-yl}- 440 [M + H]⁺ methanone(E9) 1-(4-Bromo-phenyl)-1-{4-[4-(3-piperidin-1- 4-bromo benzoic acid MS(ES+) m/e yl-propoxy)-benzyl]-piperazin-1-yl}- 500/502 [M + H]⁺methanone (E10) 1-Benzofuran-2-yl-1-{4-[4-(3-piperidin-1-yl-2-benzofuran MS (ES+) m/e propoxy)-benzyl]-piperazin-1-yl}- carboxylicacid 462 [M + H]⁺ methanone (E11)

EXAMPLE 121-Benzo[1,3]dioxol-5-yl-1-{4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepan-1-yl}-methanone(E12)

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane (D4) (100 mg,0.30 mmol) was dissolved in dichloromethane (5 ml) and treatedsequentially with benzo[1,3]dioxole-5-carboxylic acid (125 mg, 0.75mmol),1,3-dicyclohexylcarbodiimide (155 mg, 0.75 mmol) and1-hydroxybenzotriazole hydrate (101 mg, 0.75 mmol). The mixture wasallowed to stir at room temperature under argon for 12 hours, dilutedwith methanol and passed down an SCX ion exchange column (2 g) elutingwith methanol followed by 0.880 ammonia/methanol (1:9). The basicfractions were combined and concentrated in vacuo to afford the titlecompound (127 mg). MS(ES+) m/e 480 [M+H]+.

EXAMPLES 13-15

Examples 13-15 (E13-E15) were prepared from Description 4 (D4) using ananalogous method to that described In Example 12 (E12) by substitutingbenzo[1,3]dioxole-5-carboxylic acid for the appropriate acid IndicatedIn the table. Example Carboxylic acid Mass Spectrum 1-Phenyl-1-{4-[4-(3-Benzoic acid MS(ES+) m/e 436 piperidin-1-yl- [M + H]⁺ propoxy)-benzyl]-[1,4]diazepan-1-yl}- methanone (E13) 1-Naphthalen-2-yl-1- Naphthalene-2-MS(ES+) m/e 486 {4-[4-(3-piperidin-1-yl- carboxylic acid [M + H]⁺propoxy)-benzyl]- [1,4]diazepan-1-yl}- methanone (E14) 1-(3,5-Dichloro-3,5-Dichloro-benzoic MS(ES+) m/e 505 phenyl)-1-{4-[4-(3- acid [M + H]⁺piperidin-1-yl- propoxy)-benzyl]- [1,4]diazepan-1-yl}- methanone (E15)

EXAMPLES 16-23

Examples 16-23 (E16-E23) were prepared from Description 4 (D4) using ananalogous method to that described in Example 12 (E12) by substitutingbenzo[1,3]dioxole-5-carboxylic acid for the aorpriate acid indicated inthe table followed by further purification by column chromatography onsilica gel eluting with a mixture of 0.880ammonia/methanol/dichloromethane (0.5:4.5:95). Example Carboxylic acidMass Spectrum 1-(4-Bromo-3-methyl- 4-Bromo-3-methyl- MS(ES+) m/e 529phenyl)-1-{4-[4-(3- benzoic acid [M + H]⁺ piperidin-1-yl-propoxy)-benzyl]- [1,4]diazepan-1-yl}- methanone (E16)1-(2-Methoxy-phenyl)- 2-Methoxy-benzoic MS(ES+) m/e 4661-{4-[4-(3-piperidin-1- acid [M + H]⁺ yl-propoxy)-benzyl]-[1,4]diazepan-1-yl}- methanone (E17) 4-(1-{4-[4-(3-Piperidin-4-Cyano-benzoic acid MS(ES+) m/e 461 1-yl-propoxy)-benzyl]- [M + H]⁺[1,4]diazepan-1-yl}- methanoyl)- benzonitrile (E18)1-(4-Fluoro-phenyl)-1- 4-Fluoro-benzoic acid MS(ES+) m/e 454{4-[4-(3-piperidin-1-yl- [M + H]⁺ propoxy)-benzyl]- [1,4]diazepan-1-yl}-methanone (E19) 1-(4-Bromo-phenyl)-1- 4-Bromo-benzoic acid MS(ES+) m/e515 {4-[4-(3-piperidin-1-yl- [M + H]⁺ propoxy)-benzyl]-[1,4]diazepan-1-yl}- methanone (E20) 1-Benzofuran-2-yl-1- Benzofuran-2-MS(ES+) m/e 476 {4-[4-(3-piperidin-1-yl- carboxylic acid [M + H]⁺propoxy)-benzyl]- [1,4]diazepan-1-yl}- methanone (E21) 1-(3,4-Dichloro-3,4-Dichloro-benzoic MS(ES+) m/e 505 phenyl)-1-{4-[4-(3- acid [M + H]⁺piperidin-1-yl- propoxy)-benzyl]- [1,4]diazepan-1-yl}- methanone (E22)1-Cyclopropyl-1-{4-[4- Cyclopropane MS(ES+) m/e 400 (3-piperidin-1-yl-carboxylic acid [M + H]⁺ propoxy)-benzyl]- [1,4]diazepan-1-yl}-methanone (E23)

EXAMPLE 241-Cyclopentyl-1-(4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-(1,4)diazepan-1-yl)-methanone(E24)

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane (D4) (100 mg,0.30 mmol) was dissolved in dichloromethane (5 ml), treated withcyclopentyl acid chloride (80 mg, 0.60 mmol), potassium carbonate (83mg, 0.60 mmol) and allowed to stir at room temperature under argon for12 hours. The reaction mixture was diluted with methanol and passed downan SCX column (2 g) eluting with methanol followed by ammonia/methanol(1:9). The basic fractions were combined and concentrated in vacuo toafford the title compound (56 mg). MS(ES+) m/e 428 [M+H]⁺.

EXAMPLE 251-Benzenesulfonyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane(E25)

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane (D4) (100 mg,0.30 mmol) was dissolved in 2-butanone (5 ml), treated with benzenesulfonyl chloride (57 mg, 0.32 mmol) and allowed to stir at roomtemperature under argon for 2 hours. The reaction mixture was dilutedwith methanol and passed down an SCX column (2 g) eluting with methanolfollowed by ammonia/methanol (1:9). The basic fractions were combinedand concentrated in vacuo to afford the title compound (91 mg). MS(ES+)m/e 472 [M+H]⁺.

EXAMPLES 26-28

(E26-E28) were prepared from Description 4 (D4) using an analogousmethod to that described in Example 25 (E25) by substitutingbenzenesulfonyl chloride for the appropriate sulfonyl chloride indicatedin the table. Example Sulfonyl Chloride Mass Spectrum 1-(Naphthalene-2-Naphthalene-2- MS(ES+) m/e 522 sulfonyl)-4-[4-(3-piperidin- sulfonyl[M + H]⁺ 1-yl-propoxy)-benzyl]- chloride [1,4]diazepane (E26)1-(4-Fluoro-benzenesulfonyl)- 4-Fluoro- MS(ES+) m/e 4904-[4-(3-piperidin-1-yl- benzenesulfonyl [M + H]⁺propoxy)-benzyl]-[1,4]diazepane chloride (E27)1-(4-Bromo-benzenesulfonyl)- 4-Bromo- MS(ES+) m/e 5524-[4-(3-piperidin-1-yl- benzenesulfonyl [M + H]⁺ propoxy)-benzyl]-chloride [1,4]diazepane (E28)

EXAMPLES 29-31

Examples 29-31 (E29-E31) were prepared from Description 4 (D4) using ananalogous method to that described in Example 25 (E25) by substitutingbenzenesulfonyl chloride for the appropriate sulfonyl chloride indicatedin the table followed by further purification by column chromatographyon silica gel eluting with a mixture of 0.880ammonia/methanol/dichloromethane (0.5:4.5:95). Example Sulfonyl ChlorideMass Spectrum 1-(3,5-Dichloro- 3,5-Dichloro- MS(ES+) m/e 540benzenesulfonyl)-4-[4- benzenesulfonyl [M + H]⁺(3-piperidin-1-yl-propoxy)- chloride benzyl]-[1,4]diazepane (E29)1-(3,4-Dichloro- 3,4-Dichloro- MS(ES+) m/e 540 benzenesulfonyl)-4-[4-benzenesulfonyl [M + H]⁺ (3-piperidin-1-yl-propoxy)- chloridebenzyl]-[1,4]diazepane (E30) 4-{4-[4-(3-Piperidin- 4-Cyano- MS(ES+) m/e497 1-yl-propoxy)-benzyl]- benzenesulfonyl [M + H]⁺ [1,4]diazepane-1-chloride sulfonyl}-benzonitrile (E31)

EXAMPLE 321-Phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone(E32)

The title compound (E32) was prepared from4-{4-[4-(1-phenyl-methanoyl)-piperazin-1-ylmethyl]-phenoxy}-piperidine-1-carboxylicacid tert-butyl ester (D7) using the method described in Description 4(D4). MS(ES+) rne 380 [M+H]⁺.

EXAMPLE 331-{4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-1-phenyl-methanone(E33)

The title compound (E33) was prepared from1-phenyl-1-{4-[4(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone(E32) and acetone using the method described in Description 1 (D1).MS(ES+) m/e 422 [M+H]⁺.

EXAMPLE 341-(4-{4-[1-(2-Methoxy-ethyl)-piperldin-4-yloxy]-benzyl}-piperazin-1-yl)-1-phenyl-methanone(E34)

1-Phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone(E32) (150 mg, 0.40 mmol) was dissolved in 2-butanone and treated with1-chloro-2-methoxy-ethane (0.08 ml, 0.80 mmol), potassium carbonate (132mg, 0.96 mmol) and potassium iodide (159 mg, 0.96 mmol). The reactionmixture was heated under reflux for 24 hours. The mixture was allowed tocool to room temperature, acidified by the addition of glacial aceticacid and passed down an SCX ion exchange column (2 g) eluting withmethanol followed by ammonia/methanol (1:9). The basic fractions werecombined and concentrated in vacuo to afford the title compound (76 mg).MS(ES+) m/e 438 [M+H]⁺.

EXAMPLES 35-37

Examples 35-37 (E35-E37) were prepared In accordance with the followinggeneral synthesis:

The appropriate acid chloride (1.1 eq) was added to a mixture of1-[4-(3-piperidin-1-yl-propoxy)phenyf]-piperazine (D11) (100 mg; 0.33mM) and potassium carbonate (55 mg; 1.5 eq) in butan-2-one (2 ml). Theresulting mixtures were stirred at room temperature for 3 hours and thenpurified on SC× ion exchange cartridges to afford the title compounds.Example Acid Chloride Mass Spectrum 1-Cyclopropyl-1-{4-[4-(3-piperidin-Cyclopropane MS (ES+) 1-yl-propoxy)-phenyl]-piperazin-1- carbonylchloride m/e 372 yl}-methanone (E35) [M + H]⁺.1-Phenyl-1-{4-[4-(3-piperidin-1-yl- Benzoyl chloride MS (ES+)propoxy)-phenyl]-piperazin-1-yl}- m/e 408 methanone (E36) [M + H]⁺.1-(3,4-Dichloro-phenyl)-1-{4-[4-(3- 3,4- MS (ES+)piperidin-1-yl-propoxy)-phenyl]- Dichlorobenzoyl m/e 477piperazin-1-yl}-methanone (E37) chloride [M + H]⁺.

EXAMPLE 38-39

Examples 38-39 (E38-E39) were prepared from1-[3-(3-piperidin-1-yl-propoxy)phenyl]-piperazine (D15) using the sameprocedure as described in Examples 36 and 37, respectively. Example MassSpectrum 1-Phenyl-1-{4-[3-(3-piperidin-1-yl-propoxy)- MS (ES+) m/ephenyl]-piperazin-1-yl}-methanone (E38) 408 [M + H]⁺.1-(3,4-Dichloro-phenyl)-1-{4-[3-(3-piperidin-1-yl- MS (ES+) m/epropoxy)-phenyl]-piperazin-1-yl}-methanone 477 [M + H]⁺. (E39)

EXAMPLES 40-42

Examples 40-42 (E40-E42) were prepared in accordance with the followinggeneral synthesis:

The appropriate sulphonyl chloride (1.1 eq) was added to a mixture of1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D11) (100 mg; 0.33mM) and potassium carbonate (55 mg; 1.5 eq) in butan-2-one (2 ml). Theresulting mixtures were stirred at room temperature for 3 hours and thenpurified on SC× ion exchange cartridges to afford the title compounds.Example Sulfonyl Chloride Mass Spectrum 1-Methanesulphonyl-4- Methanesulfonyl MS (ES+) m/e [4-(3-piperidin-1-yl-propoxy)- chloride 382 [M +H]⁺. phenyl]-piperazine (E40) 1-Benzenesulphonyl-4-[4-(3- Benzenesulfonyl MS (ES+) m/e piperidin-1-yl-propoxy)-phenyl]- chloride 444 [M +H]⁺. piperazine (E41) 1-(3,4-Dichloro 3,4- MS (ES+) m/ebenzenesulphonyl)-4-[4-(3- Dichlorobenzene 513 [M + H]⁺.piperidin-1-yl-propoxy)- sulfonyl chloride phenyl]-piperazine (E42)

EXAMPLES 43-45

Examples 43-45 (E43-E45) were prepared from1-[3-(3-piperidin-1-yl-propoxy)-phenyI]-piperazine (D15) using the sameprocedure as described in Examples 40, 41 and 42, respectively. ExampleMass Spectrum 1-Methanesulphonyl-4-[3-(3-piperidin-1-yl- MS (ES+) m/e382 propoxy)-phenyl]-piperazine (E43) [M + H]⁺.1-Benzenesulphonyl-4-[3-(3-piperidin-1-yl- MS (ES+) m/e 444propoxy)-phenyl]-piperazine (E44) [M + H]⁺. 1-(3,4-Dichlorobenzenesulphonyl)-4-[3-(3- MS (ES+) m/e 513piperidin-1-yl-propoxy)-phenyl]-piperazine (E45) [M + H]⁺.

EXAMPLES 46-47

Examples 46-47 (E46-E47) were prepared in accordance with the followinggeneral synthesis:

The appropriate isocyanate (1.1 eq) was added to1-[4-(3-piperidin-1-yl-propoxyy phenyl]-piperazine (D11) (100 mg; 0.33mM) in butan-2-one (2 ml). The resulting mixtures were stirred at roomtemperature for 3 hours and then purified on SCX ion exchange cartridgesto afford the title compounds. Mass Example Isocyanate Spectrum4-[4-(3-Piperidin-1-yl-propoxy)- Isocyanatobenzene MS (ES+) m/e phenyl]piperazine-1-carboxylic 423 [M + H]⁺. acid phenylamide (E46)4-[4-(3-Piperidin-1-yl-propoxy)- 3,4-Dichloro MS (ES+) m/e phenyl]piperazine-1-carboxylic isocyanato benzene 492 [M + H]⁺. acid(3,4-dichloro-phenyl)-amide (E47)

EXAMPLE 48 4-[4-(3-Piperidin-1-yl-propoxy)-phenyl]piperazine-1-carboxylic acid cyclopropylamide (E48)

To a solution of 1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine(D11) (150 mg, 0.49 mM) In dry dichloromethane (3 ml) was added dropwise a 20% solution of phosgene in toluene (0.5 ml; ˜2 eq) and theresulting mixture stirred for 1 hour. The solvent was removed byevaporation and the resulting white powder dissolved in drydichloromethane (4 ml). Triethylamine (0.14 ml: 2 eq) was added followedby cyclopropylamine (0.1 ml; 3 eq) and the mixture stirred for 18 hours.The solvent was removed by evaporation in vacuo and the residue purifiedon a silica column eluting with 3% methanol in dichloromethane to affordthe title compound as a white solid (155 mg) MS (ES+) m/e 387 [M+H]⁺.

EXAMPLES 49-50

Examples 49-50 (E49-E50) were prepared from1-[3-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D15) using the sameprocedure as described in Examples 46 and 47, respectively. Example MassSpectrum 4-[3-(3-Piperidin-1-yl-propoxy)-phenyl] MS (ES+) m/e 423piperazine-1-carboxylic acid phenylamide (E49) [M + H]⁺.4-[3-(3-Piperidin-1-yl-propoxy)-phenyl] MS (ES+) m/e 492piperazine-1-carboxylic acid (3,4-dichloro- [M + H]⁺. phenyl)-amide(E50)

EXAMPLE 511-(3,4-Dichloro-phenyl)-4-[4-(3-Piperidin-1-yl-propoxy)-phenyl]piperazine (E51)

Tris(dibenzylidineacetone) di palladium (0) (5 mol %; 23 mg) was addedto a mixture of 1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (Dl1)(150 mg; 0.49 mmol), 3,4-dichloro bromo benzene (160 mg; 1.2 eq), sodiumtert-butoxide (71 mg; 1.1 eq) and racemic2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (7.5 mol %; 24 mg) in drytoluene (3 ml). The resulting mixture was heated at reflux under argonfor 18 hours. The reaction was allowed to cool to room temperature anddiluted with ethyl acetate (10 ml). The resulting solids were removed byfiltration and the filtrate evaporated in vacuo. The residue waspurified by column chromatography on silica eluting with 3% methanol indichloromethane to afford the title compound as a buff solid (45 mg) MS(ES+) m/e 448 [M+H]⁺.

EXAMPLE 52 1-(3,4-Dichloro-phenyl)-4-[3-(3-Piperidin-1-ylpropoxy)-phenyqpiperazine (E52)

The title compound (E52) was prepared from1-[3-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D15) using the samemethod as described in Example 51 (E51). MS (ES+) m/e 448 [M+H]⁺.

EXAMPLE 535-Fluoro-1-methyl-3-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}-1H-indole(E53)

A solution of 5-fluoro-1-methyl-1H-Indole-3-carboxylic acid [WO 0071537A1] (35 mg) and 1-(4(3-(1-plperidinyl)propyl]oxyyphenyl)piperazine (D11)(50 mg) in dichloromethane (1 ml) was treated withbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (94.4mg) and heated in a microwave (CEM™ Discover microwave) at 120° C. for 5min. The reaction mixture was concentrated In vacuQ and purified on aSC× cartridge (2 g) eluting with methanol-aqueous ammonia (10:1)followed by mass directed auto preparative HPLC to give the titlecompound (12 mg). LCMS RT=2.49 min, 478 (M+H)⁺

EXAMPLES 54-61

The following compounds were prepared in an analogous manner to theprocess described for E53 from D11 and a known appropriate acid, withthe exception of Example 57 which was prepared from D11 and D17. RT MassIon Example Structure (min) (M + H)⁺ 54

2.37 448 450 55

2.26 464 56

2.41 478 57

2.40 539 541 58

2.32 474 59

2.56 539 541 60

2.54 546 61

2.80 536

EXAMPLE 62(1-Methyl-3-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}-phenyl)-1-piperazinyl]carbonyl}-1H-indol-2-yl)aceticacid (E62)

A solution of ethyl(1-methyl-3-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}-1H-indol-2-yl)acetate(E60) [54 mg] in methanol [6 ml] and water [0.8 ml] was treated with 2Nsodium hydroxide [0.46 ml] and was heated under reflux for 2 h. Thereaction mixture was quenched with hydrochloric acid [10 ml] at roomtemperature. The reaction mixture was concentrated in vacuo andpartitioned between ethyl acetate and water. The organic phase was driedand concentrated in vacuo to give the title compound (20 mg). LCMSRT=2.35 min, 518 (M+H)⁺

EXAMPLE 631-(1-Naphthoyl)-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazinetrifluoroacetate (E63)

E63a: 4-[4-(1-Naphthoyl)piperazin-1-yl]phenol

To a stirring mixture of 4-(1-piperazinyl)phenol (5.54 g) andtriethylamine (10.83 ml) in dichloromethane (140 ml) was added dropwise,1-naphthalenecarbonyl chloride (9.83 ml). The resulting reaction mixturewas stirred under a nitrogen atmosphere for 3 h. The mixture waspartitioned between dichloromethane and water and the organic phase waswashed with saturated brine, dried (MgSO₄) and evaporated to dryness.The residue was suspended in 6:4 tetrahydrofuran-methanol (370 ml) andtreated with a saturated solution of potassium carbonate in methanol (45ml). The mixture was stirred at room temperature under a nitrogenatmosphere for 20 h. The solvent was evaporated and the residue waspartitioned between dichloromethane and water. The organic phase waswashed with saturated brine, dried (MgSO₄) and evaporated to give an oil(15.5 g), part of which (14.5 g) was purified by chromatography on asilica SPE bond elut cartridge eluting with 10% -80% ethylacetate—cyclohexane gradient to give the title compound (8.9 g). LCMSRT=2.97 min.

E63b: 1-[4-(3-Chloropropoxy)phenyl]-4-(1-naphthoyl)piperazine

Was prepared from 4-[4-(1-naphthoyl)piperazin-1-yl]phenol (E63a) and1-bromo-3-chloropropane using the same method described in Description 9LCMS RT=3.59 min

E63c: 1-(1-Naphthoyl)-4-[4-(3-piperidin-1-ylpropoxy)phenyl]piperazinetrifluoroacetate

1-[4-(3-Chloropropoxy)phenyl]-4-(1-naphthoyl)piperazine (E63b) (27 mg)piperidine (0.033 ml), potassium carbonate (46 mg), potassium iodide (56mg) in 2-butanone (2 ml) was heated to reflux for 36 h. The solvent wasremoved at room temperature by a stream of nitrogen gas. The residue wasdissolved In water and dichloromethane. The organic layer was separated,concentrated and purified by mass directed preparative HPLC to give thetitle compound (23 mg). LCMS RT=2.15 min, ES+ve m/z 458 (M+H)⁺.

EXAMPLES 64-75

Examples 64-75 were prepared in an array format using the same methoddescribed in Example 63c from1-[4-(3-chloropropoxy)phenyl]-4-(1-naphthoyl)piperazine (0.067 mmol),the appropriate secondary amine (5.0 eq), potassium carbonate (5.0 eq),and potassium iodide (5.0 eq) in 2-butanone (2 ml). The products werepurified by mass directed auto-preparative HPLC to provide the compoundsas TFA salts. RT Mass Ion Example Structure (min) (M + H)⁺ 64

2.76 500 65

2.63 472 66

2.55 476 67

2.27 486 68

2.66 472 69

2.58 458 70

2.71 485.73 71

2.22 472 72

2.22 472 73

2.26 514 74

2.35 500 75

2.24 486

EXAMPLE 765-Fluoro-1-methyl-3-[(4-{4-[3-(2-methylpiperldin-1-yl)propoxy]phenyl}piperazin-1-yl)carbonyl]-1H-indole(E76)

E76a: 1,1-Dimethylethyl4-(4-{[3-(2-methyl-l-piperidinyl)propyl]oxy}phenyl)-1-piperazinecarboxylate

1,1-Dimethylethyl4-{4-[(3-chloropropyl)oxy]phenyl})1-piperazinecarboxylate (D9) (1.6 g),was dissolved in 2-butanone (10 ml). Potassium carbonate (1.38 g) and acatalytic amount of potassium iodide were added, followed by2-methylpiperidine (0.99 g). The mixture was heated at reflux for 72 hunder nitrogen. The reaction mixture was diluted with water andextracted with dichloromethane. The organic phases were separated usinga hydrophobic frit, combined and evaporated in vacuo. The residue waspurified on a 100 g silica SPE bond elut cartridge, eluting with agradient of 0% to 20% [0.880 ammonia-methanol (1:9)]-dichloromethanemixtures, to give the itile compound (1.66 g). LCMS RT=2.48 min.E76b: 1-(4-{[3-(2-Methyl-1-piperidinyl)propyl]oxy}phenyl)piperazine

1,1-Dimethylethyl 4-(4-{[3-(2-methyl-1-piperidinyl)propyl]oxy}phenyl)-1-piperazinecarboxylate (E76a) (1.66 g) was dissolvedin dry dichloromethane (25 ml) and stirred under nitrogen. 50%Trifluoroacetic acid in dichloromethane (5 ml) was added, and themixture was stirred at room temperature for 4 h. Saturated sodiumbicarbonate solution was then added and the mixture was extracted withdichloromethane. The organic phase was separated using a hydrophobicfrit, and evaporated in vacuo, however, most of the product was in theaqueous phase. The product was removed from the aqueous phase using anOASIS cartridge, washing with water and eluting with methanol, andfurther purified using an aminopropyl bond elut cartridge, eluting withdichloromethane and then SCX cartridge, eluting with 50% [0.880ammonia-methanol (1:9)]-dichloromethane to give the title compound (0.94g). LCMS RT=1.01 min, ES+ve m/z=318 (M+H)⁺

E76c:5-Fluoro-1-methyl-3-[(4-{4-[3-(2-methylpiperidin-1-yl)propoxy]phenyl}piperazin-1-yl)carbonyl]-1H-indole

A solution of 5-fluoro-1-methyl-1H-indole-3-carboxylic acid (19.3 mg)and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (56 mg) in DMF (1 ml) and diisopropylethylamine(0.035 ml) was stirred for 10 min before1-{4-[3-(2-methylpiperidln-1-yl)propoxy]phenyl}piperazine (E76b) (21.3mg) in DMF (0.5 ml) was added. The mixture was stirred for 18 h and thenconcentrated under reduced pressure. The residue was purified by SPE ionexchange chromatography on an SCX-2 cartridge (1 g). The cartridge waswashed with methanol (3 ml) and the product eluted with 2M ammonia inmethanol (2.5 ml), to give the title compound (15 mg) LCMS RT=2.42 min,ES+ve m/z 493 (M+H)⁺.

EXAMPLES 77-224

Examples 77 to 224 were prepared in an array format in vials using asolution of the appropriate carboxylic acid (0.1 mmol) in DMF (0.5 ml)and a solution of O(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (TBTU) (0.15 mmol) in DMF (0.5 ml) anddiisopropylethylamine (0.2 mmol). Each vial was shaken manually andstood for 10 min, before a solution of the appropriate piperazine(selected from D18-D23 or D46 in the case of Example 99) (0.067 mmol) inDMF (0.5 ml) was added to each reaction mixture. The vials were left tostand overnight for approximately 18 h at room temperature. Eachsolution was then added to the top of a preconditioned SCX-2 SPEcartridge (1 g). The cartridge was washed with methanol (3 ml) and theproduct eluted with 2M ammonia in methanol (2.5 ml), into pre-weighedvials. The solutions were evaporated to dryness on the genevac toprovide the products (Examples 77-222). Examples 151, 154, 162-171 and206-222 were further purified by mass directed auto-preparative HPLC toprovide the products as trifluoroacetate salts. RT Mass Ion ExampleStructure (min) (M + H)⁺ 77

2.36 438 78

2.52 464 79

2.55 466 80

2.44 452 81

2.74 484 82

2.52 436 83

2.74 480 84

2.58 476 85

2.50 442 444 86

2.39 444 87

2.50 434 88

2.36 485 89

2.58 480 90

2.34 480 91

2.66 480 92

2.23 456 93

2.76 464 94

2.24 424 95

2.16 468 96

1.87 463 97

1.96 463 98

1.85 467 99

2.11 461 100

2.37 484 101

2.11 485 102

2.05 473 475 103

2.07 460 462 104

2.07 478 105

2.18 476 478 106

2.13 466 107

2.05 440 108

2.20 450 109

2.31 464 110

2.31 464 111

2.29 464 112

2.22 462 113

2.07 436 114

2.07 436 115

2.12 476 478 116

2.13 448 117

2.26 480 118

2.29 478 119

2.15 485

120

2.52 472 121

2.52 452 122

2.63 475 123

2.53 464 124

2.53 480 125

2.60 464 126

2.47 468 127

2.59 464 128

2.61 537 129

2.37 475 130

2.58 534 131

2.66 518 520 132

2.54 494 133

2.76 504 134

2.60 478 135

2.60 517 136

2.65 588 137

2.83 579 138

2.60 476 139

2.63 536 140

2.69 542 141

2.62 528 530 142

2.68 589 143

2.61 521 144

2.58 478 145

2.70 492 146

2.81 506 147

2.77 522 148

2.77 506 149

2.59 464 150

2.57 464 151

2.27 486 152

2.60 478 153

2.63 494 154

2.36 466 155

2.36 466 156

2.65 478 157

2.54 464 158

2.40 450 159

2.42 561 160

2.42 561 161

2.51 500 502 162

2.66 492 163

2.60 528 530 164

2.54 522 165

2.51 462 166

2.76 565 167

2.55 504 168

2.51 464 169

2.67 490 170

2.45 480 171

2.57 504 506 172

2.63 478 173

2.65 494 174

2.69 478 175

2.56 482 176

2.49 500 502 177

2.66 478 178

2.55 514 516 179

2.47 448 180

2.72 551 181

2.52 560 182

2.47 489 183

2.54 490 184

2.47 450 185

2.60 476 186

2.39 466 187

2.53 491 188

2.63 478 189

2.64 494 190

2.68 478 191

2.58 482 192

2.55 464 193

2.44 450 194

2.47 500 502 195

2.66 478 196

2.44 508 197

2.44 448 198

2.71 551 199

2.52 560 200

2.46 489 201

2.50 490 202

2.46 450 203

2.62 476 204

2.39 466 205

2.52 490 492 206

2.40 508 207

2.37 496 208

2.35 478 209

2.27 464 210

2.37 504 506 211

2.26 514 516 212

2.34 528 530 213

2.00 514 214

2.28 522 215

2.26 462 216

2.57 574 217

2.30 503 218

2.30 504

1. A compound of formula (I):

wherein: R¹ represents hydrogen, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, aryl, heterocyclyl, heteroaryl, —C₁₋₆ alkyl-aryl, —C₁₋₆ alkyl-heteroaryl, —C₁₋₆ alkyl-heterocyclyl, -aryl-aryl, -aryl-heteroaryl, -aryl-heterocyclyl, -heteroaryl-aryl, -heteroaryl-heteroaryl, -heteroaryl-heterocyclyl, -heterocyclyl-aryl, -heterocyclyl-heteroaryl, -heterocyclyl-heterocyclyl, wherein R¹ may be optionally substituted by one or more substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, COOR¹⁵, cyano, —C₁₋₆ alkyl-cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, fluoromethoxy, difluoromethoxy, C₁₋₆ alkyl (optionally substituted by a COOR¹⁵ group), C₂₋₆ alkenyl (optionally substituted by a COOR¹⁵ group), C₂₋₆ alkynyl (optionally substituted by a COOR¹⁵ group), C₁₋₆ alkoxy (optionally substituted by a COOR¹⁵ group), pentafluoroethyl, C₁₋₆alkoxy, C₂₋₆ alkenoxy, aryl, arylC₁₋₆ alkyl, —CO-aryl (optionally substituted by a halogen atom), —CO-heteroaryl, —C₁₋₆ alkyl-CO-aryl, arylC₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, sulfonyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC₁₋₆ alkyl, aryloxy, C₁₋₆ alkylsulfonamido, C₁₋₆ alkylamido, C₁₋₆ alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆ alkylamidoC₁₋₆ alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC₁₋₆ alkyl, arylcarboxamidoC₁₋₆ alkyl, aroyl, aroylC₁₋₆ alkyl, arylC₁₋₆ alkanoyl, or a group —COR¹⁵, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —NR¹⁵SO₂R¹⁶ or —SO₂NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ independently represent hydrogen, C₁₋₆ alkyl or C₃₋₈ cycloalkyl or together may be fused to form a 5- to 7-membered non-aromatic heterocyclic ring optionally interrupted by an O or S atom and optionally substituted by a halogen, C₁₋₆ alkyl or —C₁₋₆ alkylC₁₋₆ alkoxy group; Z represents a bond, CO, —CON(R¹⁰)— or SO₂, such that when R¹ represents hydrogen, Z represents CONR¹⁰; p is 1 or 2; m, n and r independently represent 0, 1 or 2; R² represents halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino or trifluoromethyl, such that when n represents 2, two R² groups may instead be linked to form a phenyl ring; R⁴ represents C₁₋₆ alkyl, such that when r represents 2, two R⁴ groups may instead be linked to form a CH₂, (CH₂)₂or (CH₂)₃ group; R¹⁰ represents hydrogen or C₁₋₆ alkyl, or R¹⁰, together with R¹ forms a heterocyclic group; R³ represents —(CH₂)_(q)—NR¹¹R¹² or a group of formula (i):

wherein q is 2, 3 or 4; R¹¹ and R¹² independently represent C₁₋₆ alkyl or C₃₋₈ cycloalkyl or together with the nitrogen atom to which they are attached represent an N-linked nitrogen containing heterocyclyl group optionally substituted by one or more R¹⁷ groups; R¹³ represents hydrogen, C₁₋₆ alkyl, —C₁₋₆ alkyl-C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-aryl or heterocyclyl; R¹⁴ and R¹⁷ independently represent halogen, C₁₋₆ alkyl, haloalkyl, OH, diC₁₋₆ alkylamino, C₁₋₆ alkoxy or heterocyclyl; f and k independently represent 0, 1 or 2; g is 0, 1 or 2 and h is 0, 1, 2 or 3, such that g and h cannot both be 0; with the proviso that when m represents 1, n and r both represent 0 and R³ represents —(CH₂)₃-N-piperidine or —(CH₂)₃-N(ethyl)₂, R¹-Z represents a group other than methyl, —CO—O—C(CH₃)₃ or benzyl; and with the proviso that when m, n and r all represent 0, p represents 1, R³ represents —(CH₂)₃-N-pyrrolidine or —(CH₂)₃-N-piperidine, R¹ represents benzyl, Z represents a group other than a bond; and with the proviso that when m, n and r all represent 0, p represents 1, R³ represents —(CH₂)₃-N-piperidine, R¹ represents isopropyl, Z represents a group other than a bond; and with the proviso that when m represents 1, n and r both represent 0, p represents 1, R³ represents —(CH₂)₃-N-piperidine, R¹ represents methyl, isopropyl, aryl or benzyl, Z represents a group other than a bond; and with the proviso that when m and n both represent 0, R³ represents —(CH₂)₃-N(ethyl)₂, p represents 1, r represents 2 and R¹ and R⁴ both represent methyl, Z represents a group other than a bond; or a pharmaceutically acceptable salt thereof.
 2. A compound according to claim 1 which is a compound of formula E1-E503 or a pharmaceutically acceptable salt thereof.
 3. A pharmaceutical composition which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 4-6. (canceled)
 7. A method of treatment of neurological diseases or inflammatory diseases of the upper respiratory tract which comprises administering to a host in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 8. A pharmaceutical composition for the treatment of neurological diseases or inflammatory diseases of the upper respiratory tract which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
 9. A pharmaceutical composition which comprises the compound of claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
 10. A pharmaceutical composition for the treatment of neurological diseases or inflammatory diseases of the upper respiratory tract which comprises the compound of claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
 11. A method of treatment of neurological diseases or inflammatory diseases of the upper respiratory tract which comprises administering to a host in need thereof an effective amount of a compound of claim 2 or a pharmaceutically acceptable salt thereof. 